Abstract: In order to improve the comprehensive diagnostic efficiency of spacecraft on orbit, a comprehensive diagnostic method is proposed based on mixed weighted and dynamic time warping (DTW) algorithms. Firstly, a mixed weighted method combining normalization and the analytic hierarchy process (AHP) is applied to determine the weighting coefficients of multivariate telemetry parameters for spacecraft. Using these weighting coefficients, comprehensive characteristic parameters representing the operational state of the spacecraft can be obtained, thereby transforming multi-parameter diagnosis into single comprehensive characteristic curve analysis. Secondly, a DTW distance calculation method is introduced, which converts the comprehensive characteristic parameter judgment into a time-series similarity measurement problem. Finally, by comparing the optimal DTW distance of comprehensive characteristic parameters with the measurement threshold, the integrated diagnostic of multiple parameters for spacecraft can be achieved. By applying the method described in this paper, a comprehensive diagnostic of the depressurization process during an astronaut’s extravehicular activity was conducted. The analysis results indicate that the method features high sensitivity, simple computation and easy implementation, providing an effective method for the diagnosis of key events and health management of spacecraft in orbit.